Immunological monitoring of calcineurin inhibitors for predicting cytomegalovirus infection in kidney transplant recipients.
BACKGROUND
The short-term results of kidney transplantation are mainly attributed to the use of calcineurin inhibitors (CNI). However, opportunistic infections and cytomegalovirus (CMV) infections remain frequent and occur in the case of overimmunosuppression. Measurement of the biological effects of CNI could provide clues to identify overimmunosuppressed kidney transplant recipients (KTR) who would subsequently develop CMV infection.


METHODS
Forty-one KTR given cyclosporine (n=18) or tacrolimus (n=23) were followed up every week during 1 month, then every month during 11 months, by measuring the patient's whole blood ability to inhibit interleukin-2 (IL-2) gene transcription and by measuring the patient's intracellular T-cell IL-2, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) production in response to polyclonal activation.


RESULTS
Cytomegalovirus infection or disease occurred in 19 patients and was significantly associated with CMV serological status D+R- and D+R+ (HR=19.6 and 6.6, respectively, P=0.0001). Immunosuppressive treatment was associated with a long-lasting decrease of all cytokines produced by the patient's T-cells. However, none of these assays taken separately at any of the time points of the follow-up allowed to predict the occurrence of a subsequent CMV infection. We only observed a weak association between cumulative low levels of the percentage of TNF-alpha producing CD8+ T cells before CMV infection and its occurrence just afterwards (HR=1.39 for 1000 unit lower, P=0.04). However, this association did not remain significant after adjustment for CMV serological status.


CONCLUSIONS
This study suggests that immunological monitoring is not better than CNI whole blood levels for diagnosis of overimmunosuppression-induced CMV infection in KTR.
Couzi
Lionel
L
Service de Néphrologie, CHU Bordeaux, Hôpital Pellegrin, CNRS-UMR 5164, 146 rue Léo Saignat, Université Bordeaux 2, INSERM U897, 146, rue Léo Saignat, Bordeaux, France.
Thiébaut
Rodolphe
R
Carron
Jean-Claude
JC
Moreau
Jean-François
JF
Merville
Pierre
P
Taupin
Jean-Luc
JL
D000328:Adult; D019540:Area Under Curve; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000009:adverse effects; D003586:Cytomegalovirus Infections / Q000175:diagnosis / Q000276:immunology*; D016903:Drug Monitoring; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic / Q000379:methods*; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011446:Prospective Studies; D015203:Reproducibility of Results; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000009:adverse effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016572:Cyclosporine; D016559:Tacrolimus